A Survey of Microglia Association with Amyloid Plaque in 3xTg Alzheimer’s Disease (3xTg-AD) Models
Board Location: #17
Discipline: Biological Sciences
Subcategory: biochemistry
Session: 1
Anthony Asante-Danso - Howard University
Co-Author(s): Mofida Abdelmageed, Penn State College of Medicine, Hershey, PA; Anirban Paul, Penn State College of Medicine, Hershey, PA
Brain aging is characterized by a progressive functional decline of cellular and molecular mechanisms that affect most living organisms. The decline of these mechanisms is the primary risk factor for a plethora of neurodegenerative diseases, including Alzheimer’s Disease (AD). In AD, extracellular deposition of amyloid-beta (Aβ) and microglial activation are critical facets that influence disease progression. Microglia, the resident immune cells of the central nervous system, play a key role in maintaining brain homeostasis. Microglia eliminate these Aβ forms through phagocytosis. Aβ clearance can be stimulated by the release of numerous proteases participating in Aβ degradation. Additionally, TREM2 modulates microglial functions by stimulating the production of anti-inflammatory cytokines, such as transforming growth factor-beta1 (TGF-β1) in response to Aβ plaques [264, 265] stimulating Aβ clearance by microglia.
Our hypothesis is that increased microglia association with endogenous amyloid plaque in AD leads to neuroinflammation, thus creating a more neurotoxic environment in the brain and further progression of AD altogether.
Aβ species induce neuroinflammation and neurodegeneration by stimulating the microglia to release pro-inflammatory cytokines and interfere with the synthesis of anti-inflammatory cytokines. TREM2 variants reduce the Aβ phagocytic ability of microglia and TGF-β1 deficit exerts a key pro-inflammatory role in AD. The absence of TREM2 can enhance Aβ pathophysiology during early AD, which can be exacerbated by decreased phagocytic Aβ clearance in later disease stages.
Understanding the association of these processes is crucial for developing therapeutic strategies aimed at modulating microglia activity to ameliorate neuroinflammation and reduce amyloid pathology in Alzheimer’s disease. Little research examines how this association of microglia and amyloid plaque differs with sex or age. To address these research gaps, we are using wild-type and triple transgenic human-induced AD models (3xTg-AD) of female and male mice to gain a strong understanding of the changes in microglia activation in brain aging and AD.
In AD, endogenous plaque accumulation is disproportionate to different brain regions. Neuropathological research studies have shown an evolution of brain Aβ accumulation that occurs initially in the cerebral areas and spreads from the neocortex to the allocortex to the brainstem, eventually reaching the cerebellum. I utilized sagittal brain sections of the Old Age 3xTg model and wild-type mice. I performed immunofluorescent staining and imaged the slides I mounted using confocal microscopy (ZEISS Zen Software).
The preliminary data could suggest that the microglia in the aged AD mice become overactive and release cytokines that exacerbate amyloid plaque formation. These plaques inevitably alter neuron communication, leading to further neurodegeneration, brain atrophy, and post-mitotic cell death.
Funder Acknowledgement(s): I would like to acknowledge Dr. Atanu Duttaroy and the NIA-HUADAR program for funding this research experience.
Faculty Advisor: Mofida Abdelmageed, Mqa5893@psu.edu
Role: Following perfusions that were handled by my mentor, I was tasked with sagittal brain sectioning, immunofluorescence/immunohistochemistry, mounting slides for confocal microscopy, and imaging with the help of my team.